Corticotropin releasing factor (“CRF”), acting through the CRF-1 receptor, is a primary mediator of stress- and anxiety-related physiological responses in humans and other mammals. Antagonists of the CRF-1 receptor, both peptides (J. Gulyas, et al., Proc. Natl. Acad. Sci. U.S.A., 92: 10575-10579 (1995) and small molecules (J. R. McCarthy, et al., Curr. Pharm. Design, 5: 289-315 (1999), have demonstrated the ability to ameliorate the effects of stressful stimuli in several animal models. CRF antagonists have been suggested to affect both anxiety and depression as well as other stress related afflictions. See F. Holsboer, J. Psychiatr. Res. 33(3): 181-214 (1999); S. C. Heinrichs, Y. Tache, Exp. Opin. Invest. Drugs 10(4): 647-659 (2001); P. J. Gilligan, et al., J. Med. Chem., 43: 1641-1660 (2000); and J. R. McCarthy, et al., Ann. Rep. Med. Chem., 34: 11-20 (1999). As such, there is a continuing need to discover novel small molecule CRF antagonists in order to treat a wide variety of human disorders including affective disorders and other stress-related illnesses.
The invention provides technical advantages, for example, the compounds are novel and are effective at modulating CRF receptors. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.